HRTX – Total Pharma Tracker

Heron initiates ph 2 study of aprepitant in redacted

Heron Therapeutics, Inc. (HRTX) today announced the initiation of the GUARDS-1 phase 2 clinical study evaluating CINVANTI (aprepitant) injectable emulsion in early hospitalized patients with *redacted* following clearance from the U.S. FDA of Heron’s Investigational New Drug (IND) application for CINVANTI for the treatment of *redacted*.

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CINVANTI is an intravenous formulation of aprepitant, a substance P/neurokinin-1 (NK1) receptor antagonist (RA) approved for use for the prevention of chemotherapy-induced nausea and vomiting in patients with cancer. Substance P, and its receptor NK1, is distributed throughout the body in the cells of many tissues and organs, including the lungs. *redacted* is associated with lower respiratory tract inflammation that often progresses to ARDS, which is associated with high mortality.

The Importance

Heron’s rationale for the investigation of CINVANTI for the treatment of *redacted* is based on multiple potential mechanisms for activity. Suppressing the cytokine storm could be a crucial step to prevent the clinical deterioration of patients with *redacted*. Administration of aprepitant injectable emulsion to these patients is expected to decrease the production and release of inflammatory cytokines mediated by the binding of substance P to NK1 receptors, which could prevent the progression of lung injury to ARDS.

Additionally, aprepitant may have direct antiviral activity. Using a computational screening approach, aprepitant was found to have the ability to form hydrogen bonds to key residues within the binding pocket of the main protease of *redacted*, which is a key enzyme required for replication. CINVANTI is approved for administration as a 2-minute intravenous injection. For these potential benefits, the plasma concentrations of aprepitant produced with the 2-minute intravenous injection of CINVANTI could provide a unique advantage over other methods of administration.

Opinion

Heron’s HTX-011 demonstrates statistically significant reductions in pain intensity following surgery

Results from the phase 2b trial Study 209 of Heron’s HTX-011 in primary unilateral total knee arthroplasty (TKA), have been published online by The Journal of Arthroplasty. The results demonstrate statistically significant reductions in pain intensity following surgery. All primary and key secondary endpoints in Study 209 were achieved. PDUFA goal date is 6/26/2020, for the resubmitted NDA of September 2019.

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Design

Study 209 was a randomized, placebo- and active-controlled, double-blind, Phase 2b clinical study in patients undergoing primary unilateral total knee arthroplasty to evaluate the analgesic efficacy, safety and pharmacokinetics of HTX-011 locally administered into the surgical site. Following a dose-escalation phase, 232 patients were randomized, and 222 patients received treatment with: (1) HTX-011 400 mg bupivacaine/12 mg meloxicam administered via instillation into the surgical site; (2) HTX-011 400 mg bupivacaine/12 mg meloxicam administered via instillation into the surgical site plus a low dose of ropivacaine solution injected into the posterior capsule; (3) bupivacaine solution 125 mg administered via multiple injections into the surgical site; or (4) placebo. Ropivacaine solution and bupivacaine solution are generically available standard-of-care local anesthetics used in the management of postoperative pain. This study included a pre-specified hierarchical testing strategy for the primary and key secondary endpoints for the HTX-011 400 mg bupivacaine/12 mg meloxicam treatment groups. The primary endpoint was pain intensity as measured by the Area Under the Curve (AUC) from 0 to 48 hours post-surgery (AUC 0-48) for HTX-011 compared to placebo.

Safety

HTX-011 was well tolerated in Study 209, with a safety profile comparable to placebo and bupivacaine solution.

Efficacy

The primary and key secondary endpoints were achieved:

HTX-011 alone and in combination with ropivacaine solution resulted in reductions of 19% and 22%, respectively, in pain intensity through 48 hours when compared to placebo (p=0.0002 and p<0.0001, respectively).
HTX-011 alone and in combination with ropivacaine solution resulted in reductions of 18% and 22%, respectively, in pain intensity through 72 hours when compared to placebo (p=0.0004 and p<0.0001, respectively).
Sensitivity analyses using patient-reported pain scores without adjustment for opioid use confirmed that HTX-011 alone and in combination with ropivacaine solution resulted in reductions of 29% and 27%, respectively, in pain intensity through 48 hours, and 28% and 26%, respectively, in pain intensity through 72 hours when compared to placebo (p≤0.0002 for both comparisons).
Sensitivity analyses using patient-reported pain scores without adjustment for opioid use confirmed that HTX-011 alone and in combination with ropivacaine solution resulted in reductions of 19% and 17%, respectively, in pain intensity through 48 hours, and 17% and 16%, respectively, in pain intensity through 72 hours when compared to bupivacaine solution (P<0.05 for both comparisons).
Total opioid consumption for HTX-011 alone or in combination with ropivacaine solution was lower over 24, 48 and 72 hours when compared to placebo or bupivacaine solution.

What Next

PDUFA goal date is 6/26/2020.

Comparative Data

Note

HTX-011, an investigational non-opioid, is a dual-acting, fixed-dose combination of the local anesthetic bupivacaine with a low dose of the nonsteroidal anti-inflammatory drug meloxicam. It is the first and only extended-release local anesthetic to demonstrate in Phase 3 studies significantly reduced pain and opioid use through 72 hours compared to bupivacaine solution, the current standard-of-care local anesthetic for postoperative pain control. HTX-011 was granted Fast Track designation from the U.S. Food and Drug Administration (FDA) in the fourth quarter of 2017 and Breakthrough Therapy designation in the second quarter of 2018. Heron submitted a New Drug Application (NDA) to the FDA for HTX-011 in October of 2018 and received Priority Review designation in December of 2018. A Complete Response Letter (CRL) was received from the FDA regarding the NDA for HTX-011 on April 30, 2019 relating to chemistry, manufacturing and controls and non-clinical information. No issues related to clinical efficacy or safety were noted. Heron resubmitted an NDA to the FDA for HTX-011 in September 2019. The Prescription Drug User Fee Act (PDUFA) goal date is June 26, 2020. A Marketing Authorisation Application (MAA) for HTX-011 was validated by the European Medicines Agency (EMA) in March 2019 for review under the Centralised Procedure. Heron’s New Drug Submission (NDS) for HTX-011 for the management of postoperative pain was granted Priority Review status by Health Canada in October 2019 and accepted by Health Canada in November 2019.

Ph 1b/2 initiated for HTX-034, Heron’s non-opioid treatment for post-operative pain

Heron Therapeutics, Inc. (HRTX) initiates phase 1b/2 trial of HTX-034, a non-opioid treatment for post-operative pain, following the clearance of Heron’s IND from the U.S. FDA. HTX-034 is formulated in the same proprietary polymer as HTX-011, and designed to provide superior and prolonged analgesia. HTX-011 has a PDUFA goal date of June 26, 2020, following Heron’s resubmitted NDA for HTX-011 in September 2019.

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HTX-034, an investigational non-opioid, is a fixed-dose combination, extended-release solution of the local anesthetic bupivacaine, the nonsteroidal anti-inflammatory drug meloxicam and an additional agent that further potentiates the activity of bupivacaine. HTX-034 is formulated in the same proprietary polymer as HTX-011. HTX-034 is designed to provide superior and prolonged analgesia and enhance the activity of the local anesthetic bupivacaine via two different mechanisms. Local administration of HTX-034 in a validated preclinical postoperative pain model resulted in sustained analgesia for 7 days.

The Importance

Opinion